Silver complexes to overcome resistance in ovarian cancer

Cancer is one of the leading causes of death worldwide, and ovarian cancer is a frequently observed type that affects women around the globe. The standard treatment for ovarian cancer consists of the use of platinum-based drugs. However, in most cases, the cancer cannot be cured, due to the development of drug resistance (the tumors become resistant to treatment), which finally leads to the death of the patients. In this way, it is of high interest to find drugs that may be able to overcome tumor resistance and enhance the survival rate of patients. Platinum drugs are used to treat different types of cancer. However, especially resistance development and severe adverse effects are related to its use, which diminishes its efficacy and patients quality of life. This led to the search for other metal-based compounds that could overcome the disadvantages of platinum complexes (or even other drugs). Gold is a metal that has been investigated for different types of cancer treatment, due to its historical use in medicine and the observation that patients treated with a gold-based therapeutic for arthritis presented low rates of cancer. However, the use of this gold-based compound for ovarian cancer has failed, further highlighting the need for a new compound to treat resistant ovarian cancer. Silver has been used by human beings throughout history mainly for the treatment of bacterial infections. This metal has been shown to be less toxic than other metals (for example when compared to platinum and gold), and many different studies have been evaluating silver-based compounds for the treatment of different types of cancer. Of note, some studies (in cell culture) have shown that silver complexes can overcome ovarian cancer resistance; however, they have never been in detail compared to its gold analogs, nor been tested in vivo. This is the basis of this project. Different silver complexes will be synthetically prepared, with different modifications in their chemical structures, to evaluate which structure will be the most promising, taking into account the stability and solubility under physiological conditions. The respective gold analogs will also be prepared, to have a complete study comparing silver vs gold with the same chemical structure. Next, for selected compounds the toxicity will be evaluated, to determine a safe dose for usage. After that, the most promising ones will be evaluated in cancer cells to elucidate their mode of action (what cellular components are affected by the complexes). At last, the best compound pair (silver/gold) will be tested for in vivo efficacy against ovarian cancer. Taken together, in this project new metal-based drugs will be developed for a possible application in the fight against resistant ovarian cancer.

Ovarian cancer is one of the deadliest cancers affecting women, largely because many patients relapse after treatment and the disease becomes resistant to standard platinum-based chemotherapy. Once this resistance develops, treatment options are very limited. This project set out to explore whether new metal-based compounds could overcome this resistance and reveal hidden weaknesses in resistant cancer cells. The study compared a series of newly designed silver- and gold-based compounds that were almost identical in structure but differed in the metal at their core. Surprisingly, these small differences led to strikingly different biological effects. While all silver compounds showed similar behavior regardless of their exact structure, the gold compounds behaved very differently from one another, even when they differed only slightly. The most important discovery was that one specific gold compound was more effective against platinum-resistant ovarian cancer cells than against non-resistant ones, a rare and valuable phenomenon known as collateral sensitivity. Instead of becoming harder to kill, the resistant cancer cells had developed a vulnerability that this compound could exploit. Detailed follow-up experiments revealed why this happens. Platinum-resistant cancer cells had already rewired their energy production: they relied heavily on sugar-based energy generation and had weakened mitochondrial function (the cell's "power plants"). The newly identified gold compound specifically blocked mitochondrial energy production. In non-resistant cells, this stress could be compensated. However, resistant cells were already operating at their metabolic limit. When their remaining energy source was disrupted, they experienced an "energy collapse" and died. Importantly, this effect was not caused by higher drug uptake, increased toxicity, or the classical cell-death pathways usually associated with metal-based drugs. Instead, the compound acted by targeting cancer cell metabolism in a highly selective way. This also explains why the compound showed good selectivity for cancer cells while sparing healthy cells. In contrast, a closely related gold compound did not show this beneficial effect. Resistant cells were able to pump it out efficiently and activate protective stress responses, highlighting how even minimal chemical changes can completely alter biological outcomes. Overall, this work demonstrates three major advances: 1. Gold- and silver-based compounds, though chemically similar, act through fundamentally different biological mechanisms. 2. Platinum-resistant ovarian cancer cells possess a previously underappreciated metabolic weakness. 3. This weakness can be selectively targeted using carefully designed gold compounds. These findings open a new direction for cancer drug development by showing that treatment resistance does not only create obstacles, it can also expose new therapeutic opportunities. The identified gold compound represents a promising starting point for future preclinical development aimed at treating patients with therapy-resistant ovarian cancer.